J. Org. Chem. 2001, 66, 727-732
727
Synthesis of Oligomers of trans-(4S,5R)-4-Carboxybenzyl 5-Methyl Oxazolidin-2-one: An Approach to New Foldamers Simone Lucarini and Claudia Tomasini* Dipartimento di Chimica “G.Ciamician” - Universita` degli Studi di Bologna, Via F. Selmi 2, 40126 Bologna, Italy
[email protected] Received July 20, 2000
The synthesis of two oligomers containing three and four residues, respectively, of trans-(4S,5R)4-carboxy 5-methyloxazolidin-2-ones is described. The monomer is obtained by starting from benzylN-Boc-(3R)-aminobutanoate, by cyclization into the corresponding trans-(2S,3R)-2-carboxybenzyl3-methyl-N-Boc-aziridine and rearrangement of the product to trans-(4S,5R)-4-carboxybenzyl-5methyloxazolidin-2-one, catalyzed by Sn(OTf)2. The oligomers are synthesized by activating the carboxy group as its pentaflourophenyl ester. The trimer and the tetramer are obtained in good yield, and their 1H NMR spectra suggest that these molecules fold in ordered structures, where the C-4 hydrogen of a ring is always close to the carbonyl of the next ring. This result shows that the 4-carboxy-5-substituted-oxazolidin-2-ones are a new class of pseudoprolines which fully control the formation of a Xaai-1-Proi peptide bond in the trans conformation and are complementary to the pseudoprolines obtained from cyclocondensation of cysteine, serine, or threonine and aldehydes or ketones, which strongly favor the Xaai-1-Proi peptide bond in the cis conformation. Introduction Gellman has suggested the term “foldamers” for novel oligomers which have a tendency to adopt a specific compact conformation.1 The main characteristics of a new foldamer should be (i) the identification of new polymeric backbones with suitable folding propensities; (ii) the introduction of interesting chemical functions in the foldamer; (iii) the discovery of an efficient synthetic pathway, which generally includes preparation of the monomers in enantiomerically pure form and optimization of the polymer synthesis. The first step in foldamer design must therefore be to identify new backbones with well-defined secondary structural preferences;2 for instance, conformationally constrained amino acids provide access to short sequences of peptide mimetics with secondary structure.3 So as good monomers for the oligomerization reaction we envisaged the trans-4-carboxymethyl-5-alkyl/aryl-oxazolidin-2-ones, whose synthesis has been recently described, starting from racemic β-amino acids.4 The key step for the preparation of these heterocycles is the rearrangement of 2-carboxymethyl-3-alkyl/aryl-tert-butyloxycarbonyl-aziridines to oxazolidin-2-ones, catalyzed by a Lewis acid (Figure 1).5 The reaction proceeds with total (1) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173 and references therein. (2) See for example: (a) Long, D. D.; Hungerford, N. L.; Smith, M. D.; Brittain, D. E. A.; Marquess, D. G.; Claridge, T. D. W.; Fleet, G. W. J. Tetrahedron Lett. 1999, 40, 2195. (b) Porter, E. A.; Wang, X.; Lee, H.-S.; Weisblum, B.; Gellman, S. H. Nature 2000, 404, 565. (c) Huck, B. R.; Langenhan, J. M.; Gellman, S. H. Organic Lett. 1999, 1, 1717. (d) Seebach, D.; Abele, S.; Gademann, K.; Guichard, G.; Hintermann, T.; Jaun, B.; Matthews, J. L.; Schreiber, J. V.; Oberer, L.; Hommel, U.; Widmer, H. Helv. Chim. Acta 1998, 81, 932. (e) Hintermann, T.; Gademann, K.; Jaun, B.; Seebach, D. Helv. Chim. Acta 1998, 81, 983. (3) (a) Toniolo, C. Janssen Chim. Acta 1993, 11, 10. (b) Stigers, K. D.; Soth, M. J.; Nowick, J. S. Curr. Opin. Chem. Biol. 1999, 3, 714. (4) Tomasini, C.; Vecchione, A. Org. Lett. 1999, 1, 2153.
Figure 1. Mechanism for the rearrangement of trans-2carboxymethyl-3-alkyl/aryl-tert-butyloxycarbonyl-aziridines to trans-4-carboxymethyl-5-alkyl/aryl-oxazolidin-2-ones.
regio- and stereoselectivity and can afford a wide range of 5-carboxyoxazolidin-2-ones, simply by changing the starting β-amino acid. These heterocycles can be considered as new pseudoprolines (ΨPro).6 This term has recently been introduced to indicate synthetic proline analogues which are usually obtained by cyclocondensation of the amino acids cysteine, threonine, or serine with aldehydes or ketones. The conformation concerning the ΨPro-preceding peptide has been studied, because the propensity of the amino acid proline for forming a Xaai-1-Proi cis peptide bond can be strongly enhanced by the introduction of a pseudoproline residue. Results and Discussion We report here the synthesis of enantiomerically pure trans-(4S,5R)-4-carboxybenzyl-5-methyl-N-Boc-oxazolidin2-one 6 (Scheme 1), whose oligomerization affords a molecule which can be envisaged as a new foldamer with (5) Ferraris, D.; Drudy, W. J., III; Cox, C.; Lectka, T. J. Org. Chem. 1998, 63, 4568. (6) (a) Wittelsberger, A.; Keller, M.; Scarpellino, L.; Patiny, L.; AchaOrbea, H.; Mutter, M. Angew. Chem., Int. Ed. 2000, 39, 1111. (b) Mutter, M.; Haack, T. Tetrahedron Lett. 1992, 33, 1589. (c) Tam, J. P.; Miao, Z. J. Am. Chem. Soc. 1999, 121, 9013.
10.1021/jo005583+ CCC: $20.00 © 2001 American Chemical Society Published on Web 01/11/2001
728
J. Org. Chem., Vol. 66, No. 3, 2001
Scheme 1.
Synthesis of Benzyl Ester 4 and N-Boc Derivative 6 of the Monomer
interesting properties. In particular, we will study the role of the carbonyl of the heterocyclic ring, which in principle should impart an ordered structure to the oligomer. The preparation of the monomer was carried out starting from the enantiomerically pure (3R)-aminobutanoic acid 1, obtained by enzymatic hydrolysis of the corresponding racemic N-phenylacetyl amide with penicyllin G acylase (PGA).7 Preferentially this enzyme hydrolyzes the L (i.e., S) enantiomer, while the R is successively hydrolyzed with 6 M HCl at reflux. The (3R)aminobutanoic acid is then transformed into 2 by protection of the amino group with Boc anhydride and sodium carbonate and of the carboxy group with benzyl bromide and triethylamine (Scheme 1). The benzyl was chosen as the protecting group of the carboxy function because it is removable by hydrogenolysis, which does not damage the heterocyclic ring. An HPLC analysis of 2 has shown that it was enantiomerically pure, and the result has been confirmed by comparing of the [R]D with the data reported in the literature.8 The aziridine 3 was obtained by formation of the dianion of 2 with LiHMDS in dry THF and cyclization with iodine.9 The reaction proceeded with the intermediate formation of the anti 2-iodo derivative which was immediately transformed into the heterocycle 3. The trans aziridine was formed with high yield and diaste(7) (a) Rossi, D.; Lucente, G.; Romeo, A. Experientia 1977, 33, 1557. (b) Soloshonok, V. A.; Svedas, V. K.; Kukhlar, V. P.; Kirilenko, A. G.; Rybakova, A. V.; Solodenko, V. A.; Fokina, N. A.; Kogut, O. V.; Galaev, I. Y.; Kozlova, E. V.; Shishkina, I. P.; Galushko, S. V. Synlett 1993, 339. (c) Soloshonok, V. A.; Fokina, N. A.; Rybakova, A. V.; Shishkina, I. P.; Galushko, S. V.; Sorochinsky, A. E.; Kukhlar, V. P.; Savchenko, M. V.; Svedas, K. V. Tetrahedron: Asymmetry 1995, 7, 1601. (d) Cardillo, G.; Tolomelli, A.; Tomasini, C. J. Org. Chem. 1996, 61, 8651. For general reviews reporting the asymmetric synthesis of β-amino acids, see: (e) Enantioselective Synthesis of β-Amino Acids; Juaristi, E., Ed., Wiley-VCH: New York, 1997. (f) Cole, D. C. Tetrahedron 1989, 50, 9517. (g) Juaristi, E.; Quintana, D.; Escalante, J. Aldrichim. Acta 1994, 27, 3. (h) Cardillo, G.; Tomasini, C. Chem. Soc. Rev. 1996, 25, 117. (8) Matthews, J. L.; Overhand, M.; Kuehnle, F. N. M.; Ciceri, P. E.; Seebach, D. Liebigs Ann., Recl. 1997, 7, 1371.
Lucarini and Tomasini
reoselectivity (90:10 diastereomeric ratio from HPLC and H NMR analysis) and was obtained pure after flash chromatography. The rearrangement to oxazolidin-2-one was performed by reaction with a catalytic amount of Sn(OTf)2 which resulted to be the chosen reagent. The required oxazolidin-2-one 4 was obtained in quantitative yield and with complete regio- and stereoselectivity and can be used without any further purification. To couple two molecules of (4S,5R)-4-carboxy-5-methyloxazolidin-2-one, we had to introduce a protecting group to the nitrogen and to activate the carboxy group. Many attempts were made in order to introduce a protecting group in quantitative yield, without damaging the heterocycle. Owing to the low reactivity of the nitrogen (which is a carbamate and not an amine), we tried to form the corresponding anion by reaction with LiHMDS at 0 °C and then to add some protecting reagents, such as Boc2O, allyl bromide, and FMOC chloride (Cbz chloride was avoided, because it is not orthogonal with the benzyl ester). The results were poor in all cases, and the protected compound was obtained in 20-30% yield only by reaction with Boc2O. By replacing LiHMDS with iPr2EtN (Hu¨nig’s base) and a catalytic amount of DMAP and performing the reaction in DMF, the desired N-Boc derivative 5 was obtained in quantitative yield. After catalytic hydrogenation in ethyl acetate, the N-protected acid 6 was obtained in 67% overall yield from 2. The introduction of an activating group on the carboxy function required some study. Ciufolini and co-workers10 described the synthesis and the coupling of (4S,5R)-4chlorocarbonyl-5-methyl-N-acetyloxazolidin-2-one, derived from threonine, by reaction of the carboxyl group with oxalyl chloride and DMF. According to the authors, the acid chloride is a reactive material and not easy to purify. In our hands, with the Boc as protecting group, the reaction afforded the desired acyl chloride in very poor yield, owing to the acid-sensitive Boc group. Indeed, in these conditions, deprotection occurs, and an unprotected acyl chloride is obtained. As Ciufolini found, this material is unstable and readily decomposes. So a pentaflourophenyl ester was synthesized, by reaction of the acid with pentafluorophenyl trifloroacetate and pyridine in DMF.11 The activated ester was obtained in quantitative yield after working up with water but could not be chromatographed (Scheme 2). The coupling with the COOH-protected monomer 4 was performed in dry DMF with iPr2EtN (2.2 equiv) and DMAP at room temperature for 2 h. The yield is around 70%, but it is very sensitive to reaction conditions and can drop to about 30%, if the reaction is not carefully carried out. In any case we never isolated any byproduct, due to the hydrolysis of an heterocyclic ring. Dimer 8 was then obtained pure after flash chromatography. The 1H NMR spectrum of the dimer 8 showed an interesting outcome. The chemical shift of the C-4 hydrogen of an heterocycle resonates at 5.49 ppm, while the other resonates at 4.59 ppm, which is roughly the 1
(9) For general reviews reporting the synthesis of aziridines, see: (a) Osborn, H. M. I.; Sweeney, J. Tetrahedron: Asymmetry 1997, 8, 1693. (b) Zwanenburg, B.; Thjis, L. Pure Appl. Chem. 1196, 68, 735. (c) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599. (d) Fanta, P. E. in Heterocyclic Compounds with Three- and Four-membered Rings; Weissberg, A., Ed.; Wiley-Interscience, New York, 1964; Part 1, p 524. (10) Xi, N.; Ciufolini, M. A. Tetrahedron Lett. 1995, 36, 6595. (11) Green, M.; Berman, J. Tetrahedron Lett. 1990, 31, 5851.
Oligomerization of 4-Carboxy-5-methyloxazolidin-2-ones
J. Org. Chem., Vol. 66, No. 3, 2001 729
Figure 2. The structure and the more representative chemical shift of dimer 9 is reported. The molecule comes from the coupling of two racemates, so that a mixture of two diastereomers is obtained.
Scheme 2.
Synthesis of the Dimer 9 Figure 3. This conformation of 8 is in agreement with the lower minimum obtained with AM1 calculations and accounts for the anomalous chemical shift of C-4 hydrogen of ring A.
Scheme 3. Synthesis of the Trioxazolidin-2-one 13 and of the Tetraoxazolidin-2-one 14
same chemical shift recorded for the monomers 4 (4.01 ppm), 5 (4.34 ppm), and 6 (4.42 ppm). To understand the reason for this strong variation in chemical shift, we had to understand whether the shifted doublet belonged to ring A or to ring B. So we synthesized the racemic dimer 9, containing a methyl and an isopropyl residue (Figure 2). A mixture of two diastereomers was obtained, so two doublets at 5.58 and 5.63 ppm and two doublets at 4.50 and 4.64 ppm were recorded. From 1H NMR decoupling experiments, we could attribute the shifted doublets to C-4 hydrogen of ring A. This anomalous chemical shift may be attributed to a rigid conformation assumed by the two oxazolidin-2-ones, which are nearly orthogonal one to the other. In this conformation, C-4 hydrogen of ring A results to be very near to the carbonyl at C-2 of ring B, which causes its strong deshielding. AM1 calculations performed on 8 confirm this prediction.12 Indeed, by rotating the two bonds between ring A and ring B, four conformations of 8 corresponding to a minimum were found. Among them, the most stable conformation13 is in agreement with our hypothesis (Figure 3). This result shows that the 4-carboxy-5-substituted-oxazolidin-2-ones are a new class of pseudoprolines which fully control the formation of a Xaai-1-Proi peptide bond in the trans conformation and are complementary to the pseudoprolines obtained from cyclocondensation of cysteine, serine, or threonine and aldehydes or ketones, which strongly favor the Xaai-1Proi peptide bond in the cis conformation.6a Bearing this result in mind, we felt that an oligomer of n elements should have n - 1 shifted doublets to be a foldamer. So we projected the synthesis of the corresponding tri- and tetra-4-carboxyoxazolidin-2-one, to verify if these oligomers had, respectively, two and three shifted doublets (Scheme 3). Some dimer 8 was hydrolyzed with trifluoroacetic acid in order to remove the Boc group. The reaction afforded the free NH 10 in quantita(12) The minimization was performed with semiempirical AM1 Hamiltonian using the integrated package MOPAC 2000. (13) The most stable conformation of dimer 8 is reported in Figure 3 and is about 4 kcal/mol more stable than the closest alternative.
tive yield, and no products obtained from the opening of the heterocycles were isolated. On the other hand, by reduction of the benzyl ester with hydrogen and palladium, the free acid 11 was obtained in quantitative yield. Both compounds can be utilized without any further purification. The acid was transformed in quantitative yield into the activated ester 12, which was stable to workup, but could not be chromatographed. The synthesis of the trimer 13 and of the tetramer 14 was performed following the procedure that we had envisaged for the synthesis of the dimer 8, in DMF in the presence of iPr2EtN and DMAP. The trioxazolidin-2-one 13 and the tetraoxazolidin-2-one 14 were obtained in 55% and 50% yield, respectively, after flash chromatography. The 1H NMR spectra of 13 and 14 showed the expected results (Figure 4): in the trimer 13, two of the three doublets of C-4 hydrogens of rings A, B, C are strongly
730
J. Org. Chem., Vol. 66, No. 3, 2001
Lucarini and Tomasini
Figure 4. 1H NMR of fully protected monomer 6 (a), dimer 8 (b), trimer 13 (c), and tetramer 14 (d). The areas regarding the ring hydrogen are reported.
deshielded and all resonate between 5.4 and 5.7 ppm, while the third resonates at 4.56 ppm. Following the same behavior, three of the four doublets of C-4 hydrogens of the tetramer 14 resonate between 5.4 and 5.7 ppm, while the fourth resonates at 4.55 ppm. From this outcome we can deduce that both the oligomers fold in ordered structures, where the C-4 hydrogens of the first rings are deshielded by the carbonyls of next rings, while the C-4 hydrogen of C-terminal rings is not deshielded, because it has no carbonyl groups nearby. Further studies are in progress on this subject. Conclusions In this paper we have shown a straightforward synthetic method for the preparation of enantiomerically
pure (4S,5R)-4-carboxybenzyl-5-methyloxazolidin-2-ones. The method is quite general and can be utilized to obtain a wide range of 4-carboxybenzyl-5-alkyl/aryl-oxazolidin2-ones. These compounds belong to the family of pseudoprolines, and their oligomerization was studied. So we have shown an approach for the preparation of a trimer and a tetramer of this heterocycle in good yield, avoiding the ring hydrolysis at all stages. 1H NMR analysis of the trimer 13 and of tetramer 14 shows that two and three doublets respectively of the C-4 hydrogens are strongly deshielded, while the doublet of the C-4 hydrogen of the C-terminal ring is not: this effect can be attributed to the deshielding effect of carbonyls of the adiacent ring, which is always close to the hydrogen, thus showing that these oligomers fold in ordered structures.
Oligomerization of 4-Carboxy-5-methyloxazolidin-2-ones
Experimental Section General. NMR spectra were recorded with spectrometers at 300 or 200 MHz (1H NMR) and at 75 or 50 MHz (13C NMR). Chemical shifts are reported in δ values relative to the solvent peak of CHCl3, set at 7.27 ppm. Infrared spectra were recorded with an FT-IR spectrometer. Melting points were determined in open capillaries and are uncorrected. HPLC analysis was performed on a liquid chromatograph equipped with a variable wavelength UV detector (deuterium lamp 190-600 nm). HPLC grade 2-propanol and hexane were used as the eluting solvents. THF was distilled from sodium benzophenone ketyl. Benzyl N-Boc-(3R)-Aminobutanoate 2. (3R)-Aminobutanoic acid hydrochloride (5 mmol, 0.52 g) was dissolved in a mixture of water (10 mL) and tert-butyl alcohol (15 mL), sodium carbonate (15 mmol, 1.59 g) and Boc anhydride (7.5 mmol, 1.64 g) were added in one portion, and the mixture was refluxed for 2 h. The mixture was cooled and acidified with 11 N HCl till pH ) 1, and then tert-butyl alcohol was removed under vacuo and replaced with ethyl acetate. The organic layer was separated, washed twice with water, and dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in acetone (10 mL), triethylamine (10 mmol, 1.4 mL) followed by benzyl bromide (5.5 mmol, 0.70 mL) was added in one portion at room temperature, and the mixture was stirred for 16 h. Water was added, acetone was removed under vacuo and replaced with ethyl acetate, the mixture was separated, and the organic layer was dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (cyclohexane/ethyl acetate 9:1 as eluant) and was obtained pure in 45% overall yield (0.69 g). Mp ) 55-57 °C (lit.8 58-59 °C). IR (film): ν ) 3367, 1728, 1678 cm-1. 1H NMR (CDCl3): δ ) 1.22 (d, 3H, J ) 6.7 Hz), 1.44 (s, 9H, t-Bu), 2.48-2.64 (m, 2H), 3.92-4.18 (m, 1H), 4.90 (bs, 1H, NH), 5.12 (s, 2H), 7.22-7.51 (m, 5H). 13 C NMR (CDCl3): δ ) 20.5, 28.4, 40.8, 43.5, 66.3, 128.1, 128.3, 128.5, 135.6, 154.9, 171.2. [R]D +17.3 (c 1, CH2Cl2) (lit.8 [R]D +17.5 (c 1, CH2Cl2). C17H25NO4 (307.4): calcd C 66.43, H 8.20, N 4.56; found C 66.38, H 8.22, N 4.58. (2S,3R)-N-Boc-2-Carboxybenzyl-3-methylaziridine 3. LiHMDS (5 mmol, 1 M soln in THF, 5 mL) was added to a stirred solution of benzyl N-Boc-(3R)-aminobutanoate 2 (2.5 mmol, 0.77 g) in dry THF (10 mL) under nitrogen atmosphere at -20 °C. The mixture was stirred 1 h and then was cooled to -60 °C, and iodine was added (3 mmol, 0.76 g) in dry THF (10 mL). The mixture was stirred 1 h, an aqueous saturated solution of ammonium thiosulfate was added, and THF was removed under reduced pressure and replaced with ethyl acetate. The organic layer was separated, washed twice with water, and dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was obtained pure in 79% yield (0.60 g) as an oil after silica gel chromatography (cyclohexane/ethyl acetate 9:1 as eluant). IR (film): ν ) 1745, 1726 cm-1. 1H NMR (CDCl3): δ ) 1.31 (d, 3H, J ) 5.1 Hz), 1.41 (s, 9H), 2.78-2.89 (m, 2H), 5.17 (2H, AB J ) 12 Hz), 7.28-7.40 (m, 5H, Ph). 13C NMR (CDCl3): δ ) 20.9, 27.8, 39.6, 41.3, 67.1, 81.6, 128.2, 128.3, 128.4, 135.0, 158.7, 168.0. [R]D +9.3 (c 0.5, CH2Cl2). C17H23NO4 (305.4): calcd C 66.86, H 7.59, N 4.59; found C 66.90, H 7.62, N 4.57. (4S,5R)-4-Carboxybenzyl-5-methyloxazolidin-2-one 4. To a stirred solution of N-Boc-aziridine 3 (1 mmol, 0.31 g) in dry methylene chloride (10 mL) was added Zn(OTf)2 (0.1 mmol, 42 mg). The mixture was stirred 4 h under nitrogen at room temperature, additional methylene chloride and 5% aqueous solution of NaHCO3 were added, the organic layer was separated, and the aqueous layer was acidified with 0.1 N aqueous HCl and extracted with methylene chloride. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was obtained pure in 90% yield (0.21 g) as an oil after silica gel chromatography (cyclohexane/ethyl acetate 7:3 as eluant). IR (CH2Cl2): ν ) 3453, 1777, 1748 cm-1. 1H NMR (CDCl3): δ ) 1.51 (d, 3H, J ) 6.3 Hz), 4.02 (d, 1H, J ) 5.1 Hz), 4.69 (dq, 1H, J ) 5.1, 6.3 Hz), 5.20 (AB, 2H, J ) 12.3 Hz), 6.73 (bs, 1H, NH), 7.24-7.33 (m, 5H, Ph). 13C NMR (CDCl3): δ ) 21.1, 27.6, 62.7, 67.8, 72.2,
J. Org. Chem., Vol. 66, No. 3, 2001 731 84.5, 128.5, 128.6, 128.7, 134.5, 148.5, 167.3, 168.2. [R]D +10.8 (c 0.5, CH2Cl2) (lit.10 [R]D +7.7 (c 0.49, CH2Cl2). C12H13NO4 (235.2): calcd C 61.27, H 5.57, N 5.95; found C 61.32, H 5.53, N 4.99. (4S,5R)-N-Boc-4-Carboxybenzyl-5-methyloxazolidin-2one 5. To a stirred solution of oxazolidin-2-one 4 (1 mmol, 0.24 g) and Boc2O (1.25 mmol, 0.27 g) in dry DMF (1 mL) were added iPr2EtN (1.1 mmol, 0.19 mL) and DMAP (0.1 mmol, 12 mg). The mixture was stirred 2 h under nitrogen at room temperature, diluted with ethyl acetate (50 mL), washed with 0.1 N aqueous HCl (2 × 30 mL), washed with 5% aqueous NaHCO3 (1 × 30 mL), dried over sodium sulfate, and concentrated in vacuo. The fully protected oxazolidin-2-one 5 was obtained pure in 95% yield (0.32 g) as an oil after silica gel chromatography (cyclohexane/ethyl acetate 9:1 as eluant). IR (Nujol): ν ) 1830, 1752, 1728 cm-1. 1H NMR (CDCl3): δ ) 1.45 (s, 9H), 1.52 (d, 3H, J ) 6.6 Hz), 4.34 (d, 1H, J ) 4.5 Hz), 4.45 (dq, 1H, J ) 4.5, 6.6 Hz), 5.22 (AB, 2H, J ) 12.3 Hz), 7.24-7.45 (m, 5H, Ph). 13C NMR (CDCl3): δ ) 21.1, 27.6, 62.7, 67.8, 72.2, 84.5, 128.5, 128.6, 128.7, 134.5, 148.5, 167.3. [R]D -14.8 (c 1.2, CH2Cl2). C17H21NO6 (335.4): calcd C 60.89, H 6.31, N 4.18; found C 66.90, H 6.33, N 4.22. (4S,5R)-N-Boc-4-Carboxy-5-methyloxazolidin-2-one 6. To a solution of benzyl ester 5 (1 mmol, 0.34 g) in ethyl acetate (10 mL) was added 10% palladium on charcoal (30 mg), and the mixture was stirred in a Parr equipment with hydrogen (3 atm) for 1 h. Then the catalyst was filtered on a Celite pad, and the mixture was concentrated. The acid 6 was obtained in quantitative yield (0.24 g) without any further purification. Mp ) 114-116 °C. IR (Nujol): ν ) 3185, 1799, 1746, cm-1. 1H NMR (CD3OD): δ ) 1.50 (s, 9H), 1.52 (d, 3H, J ) 6.2 Hz), 4.43 (d, 1H, J ) 4.4 Hz), 4.58 (dq, 1H, J ) 4.4, 6.2 Hz). 13C NMR (CD3OD): δ ) 21.2, 28.0, 63.9, 74.5, 85.4, 150.2, 153.2, 171.7. [R]D -16.2 (c 0.8, methanol). C10H15NO6 (245.2): calcd C 48.98, H 6.17, N 5.71; found C 49.02, H 6.21, N 5.74. Fully Protected Dioxazolidin-2-one 8. To a stirred solution of acid 6 (0.5 mmol, 123 mg) in dry DMF (1 mL) was added pyridine (0.55 mmol, 50 µL) followed by pentafluorophenyl triflouroacetate (0.63 mmol, 130 µL). The reaction was allowed to stir for 45 min at room temperature, diluted with ethyl acetate (50 mL), washed with 0.1 N aqueous HCl (2 × 30 mL), washed with 5% aqueous NaHCO3 (1 × 30 mL), dried over sodium sulfate, and concentrated in vacuo. The pentaflourophenyl ester 7 was obtained in quantitative yield (206 mg), but could not be purified by silica gel chromatography. 1H NMR (CDCl ): δ ) 1.51 (s, 9H), 1.62 (d, 3H, J ) 6.3 Hz), 3 4.65-4.71 (m, 2H). 13C NMR (CDCl3): δ ) 21.2, 27.6, 62.3, 72.1, 85.7, 136.2, 139.2, 139.6, 142.6, 148.1, 150.1, 164.8. To a stirred solution of benzyl ester 5 (0.45 mmol, 106 mg), iPr2EtN (0.9 mmol, 263 µL), and DMAP (0.05 mmol, 6 mg) in dry DMF (1 mL) was added the pentaflourophenyl ester 7 (0.5 mmol, 206 mg) in dry DMF (1 mL) in one portion. The reaction was allowed to stir for 2 h at room temperature, diluted with ethyl acetate (50 mL), washed with 0.1 N aqueous HCl (2 × 30 mL), washed with 5% aqueous NaHCO3 (1 × 30 mL), dried over sodium sulfate, and concentrated in vacuo. The dioxazolidin-2-one 8 was obtained pure in 70% yield (146 mg) as a waxy solid after silica gel chromatography (cyclohexane/ethyl acetate 9:1 as eluant). IR (Nujol): ν ) 1826, 1795, 1750, 1718 cm-1. 1H NMR (CDCl3): δ ) 1.52 (s, 9H), 1.55 (d, 3H, J ) 6.2 Hz), 1.59 (d, 3H, J ) 6.6 Hz), 4.45 (dq, 1H J ) 2.2, 6.2 Hz), 4.61 (d, 1H, J ) 3.5 Hz), 4.68 (dq, 1H, J ) 3.5, 6.6 Hz), 5.21 (AB, 2H, J ) 11.8 Hz), 5.51 (d, 1H, J ) 2.2 Hz), 7.22-7.49 (m, 5H). 13C NMR (CDCl3): δ ) 20.6, 21.2, 27.8, 61.1, 61.7, 68.6, 72.5, 74.7, 84.5, 128.5, 128.7, 128.9, 133.9, 149.2, 150.3, 151.8, 167.0, 168.0. [R]D -64.2 (c 0.7, CH2Cl2). C22H26N2O9 (462.5): calcd C 57.14, H 5.67, N 6.06; found C 57.19, H 5.62, N 6.04. Dioxazolidin-2-one NH 10. To a stirred solution of fully protected dioxazolidin-2-one 8 (0.2 mmol, 92 mg) in dry dichloromethane (10 mL) was added triflouroacetic acid (1.8 mmol, 0.45 mL). The reaction was allowed to stir for 3 h at room temperature, washed with 5% aqueous NaHCO3 (2 × 10 mL), dried over sodium sulfate, and concentrated in vacuo. The N-deprotected dioxazolidin-2-one 10 was obtained pure in 95% yield (69 mg) as a waxy solid after silica gel chromatography
732
J. Org. Chem., Vol. 66, No. 3, 2001
(cyclohexane/ethyl acetate 7:3 as eluant). IR (CH2Cl2): ν ) 3431, 1784, 1772, 1714 cm-1. 1H NMR (CDCl3): δ ) 1.56 (d, 3H, J ) 6.4 Hz), 1.60 (d, 3H, J ) 6.4 Hz), 4.59 (d, 1H, J ) 4.2 Hz), 4.67 (dq, 1H, J ) 4.2, 6.4 Hz), 4.83 (dq, 1H, J ) 2.2, 6.4 Hz), 4.90 (d, 1H, J ) 2.2 Hz), 5.23 (AB, 2H, J ) 12.2 Hz), 5.81 (s, 1H, NH), 7.24-7.55 (m, 5H, Ph). 13C NMR (CDCl3): δ ) 20.5, 21.2, 60.2, 61.5, 68.5, 74.8, 75.6, 128.5, 128.8, 128.9, 134.1, 144.4, 162.1, 167.1, 169.9. [R]D -23.0 (c 0.4, CH2Cl2). C17H18N2O7 (362.3): calcd C 56.35, H 5.01, N 7.73; found C 56.42, H 5.08, N 7.69. Dioxazolidin-2-one COOH 11. To a solution of fully protected dioxazolidin-2-one 8 (0.2 mmol, 92 mg) in ethyl acetate (10 mL) was added 10% palladium on charcoal (10 mg), and the mixture was stirred in a Parr equipment with hydrogen (3 atm) for 1 h. Then the catalyst was filtered on a Celite pad, and the mixture was concentrated. The acid 11 was obtained pure in quantitative yield (74 mg) without any further purification. IR (CH2Cl2): ν ) 3437, 1827, 1807, 1722 cm-1. 1H NMR (CD3OD): δ ) 1.48 (s, 9H), 1.53 (d, 6H, J ) 6.6 Hz), 1.57 (d, 3H, J ) 6.3 Hz), 4.58 (d, 1H J ) 3.3 Hz), 4.74 (dq, 1H, J ) 2.5, 6.3 Hz), 4.82 (dq, 1H, J ) 3.3, 6.3 Hz), 5.59 (d, 1H, J ) 2.5 Hz), 13C NMR (CDCl3): δ ) 20.7, 21.3, 27.9, 61.1, 62.0, 73.0, 75.0, 84.9, 152.1, 168.1. [R]D -101.8 (c 0.2, CH2Cl2). C15H20N2O9 (372.3): calcd C 48.39, H 5.41, N 7.52; found C 48.38, H 5.44, N 7.55. Fully Protected Trioxazolidin-2-one 13: To a stirred solution of acid 11 (0.1 mmol, 37 mg) in dry DMF (1 mL) was added pyridine (0.11 mmol, 11 µL) followed by pentafluorophenyl triflouroacetate (0.13 mmol, 32 µL). The reaction was allowed to stir for 45 min at room temperature, diluted with ethyl acetate (30 mL), washed with 0.1 N aqueous HCl (2 × 30 mL), washed with 5% aqueous NaHCO3 (1 × 30 mL), dried over sodium sulfate, and concentrated in vacuo. The pentaflourophenyl ester 12 was obtained in quantitative yield (54 mg), but could not be purified by silica gel chromatography. 1H NMR (CDCl ): δ ) 1.51 (s, 9H), 1.59 (d, 3H, J ) 6.3 Hz), 3 1.71 (d, 3H, J ) 6.0 Hz), 4.53 (dq, 1H, J ) 2.2, 6.3 Hz), 4.804.95 (m, 2H), 5.51 (d, 1H, J ) 2.2 Hz). 13C NMR (CDCl3): δ ) 20.6, 21.2, 27.8, 60.8, 61.8, 72.8, 74.6, 85.2, 136.4, 139.7, 142.5, 150.8, 151.3, 163.9, 168.0. To a stirred solution of (4S,5R)-4-carboxybenzyl-5-methyloxazolidin-2-one 4 (0.09 mmol, 21 mg), iPr2EtN (0.2 mmol, 57 µL), and DMAP (2 mg) in dry DMF (1 mL) was added pentaflourophenyl ester 12 (0.1 mmol, 54 mg) in dry DMF (1 mL) in one portion. The reaction was allowed to stir for 3 h at room temperature, diluted with ethyl acetate (50 mL), washed
Lucarini and Tomasini with 0.1 N aqueous HCl (2 × 30 mL), washed with 5% aqueous NaHCO3 (1 × 30 mL), dried over sodium sulfate, and concentrated in vacuo. The trioxazolidin-2-one 13 was obtained pure in 55% yield (29 mg) as a white solid after silica gel chromatography (cyclohexane/ethyl acetate 9:1 as eluant). Mp ) 8385 °C (dec). IR (CH2Cl2): ν ) 1832, 1786, 1747, 1720 cm-1. 1H NMR (CDCl3): δ ) 1.51 (s, 9H), 1.59 (d, 3H, J ) 6.6 Hz), 1.61 (d, 6H, J ) 6.6 Hz), 4.56 (d, 1H, J ) 3.6 Hz), 4.63-4.70 (m, 3H), 5.20 (AB, 2H, J ) 12.0 Hz), 5.47 (d, 1H, J ) 2.1 Hz), 5.63 (d, 1H, J ) 1.8 Hz), 7.24-7.51 (m, 5H). 13C NMR (CDCl3): δ ) 20.7, 21.3, 27.9, 61.0, 62.0, 68.8, 72.7, 75.2, 84.5, 128.6, 128.8, 129.1, 133.9, 148.6, 151.8, 152.2, 166.8, 168.4, 176.6. [R]D -123.0 (c 0.6, CH2Cl2). C27H31N3O12 (589.6): calcd C 55.01, H 5.30, N 7.13; found C 55.08, H 5.33, N 7.08. Fully Protected Tetraoxazolidin-2-one 14. To a stirred solution of dioxazolidin-2-one NH 10 (0.09 mmol, 33 mg), iPr2EtN (0.2 mmol, 57 µL), and DMAP (2 mg) in dry DMF (1 mL) was added pentaflourophenyl ester 12 (0.1 mmol, 54 mg) in dry DMF (1 mL) in one portion. The reaction was allowed to stir for 3 h at room temperature, diluted with ethyl acetate (50 mL), washed with 0.1 N aqueous HCl (2 × 30 mL), washed with 5% aqueous NaHCO3 (1 × 30 mL), dried over sodium sulfate, and concentrated in vacuo. The tetraoxazolidin-2-one 14 was obtained pure in 50% yield as a white solid after silica gel chromatography (cyclohexane/ethyl acetate 9:1 as eluant). Mp ) 94-97 °C (dec). IR (CH2Cl2): ν ) 1827, 1786, 1751, 1722, 1607 cm-1. 1H NMR (CDCl3): δ ) 1.52 (s, 9H), 1.59 (d, 6H, J ) 6.6 Hz), 1.63 (d, 3H, J ) 6.3 Hz), 1.67 (d, 3H, J ) 6.3 Hz), 4.55 (d, 1H, J ) 3.3 Hz), 4.58-4.73 (m, 3H), 4.87 (dq, 1H, J ) 1.8, 6.3 Hz), 5.21 (AB, 2H, J ) 11.8 Hz), 5.47 (d, 1H, J ) 1.5 Hz), 5.57 (d, 1H, J ) 1.5 Hz), 5.64 (d, 1H, J ) 1.8 Hz), 7.227.49 (m, 5H). 13C NMR (CDCl3): δ ) 20.7, 21.3, 28.0, 61.0, 61.1, 61.2, 62.0, 68.6, 72.6, 75.2, 75.4, 75.8, 84.5, 128.6, 128.8, 129.1, 133.9, 146.5, 156.5, 156.8, 166.7, 166.9, 167.2, 172.0, 177.7. [R]D -142.0 (c 0.7, CH2Cl2). C32H36N4O15 (716.7): calcd C 53.63, H 5.06, N 7.82; found C 53.59, H 5.00, N 7.84.
Acknowledgment. This work was supported in part by M.U.R.S.T. Cofin ’98 (Roma) and by University of Bologna (funds for Selected Research Topics). Supporting Information Available: 1H NMR spectra of monomer 5, and oligomers 8, 9, 13, and 14. This material is available free of charge via the Internet at http://pubs.acs.org. JO005583+
